Many human tumors express MICA and MICB proteins as a result of cellular stress, which can activate NKG2D receptors on NK cells, marking tumor cells for elimination. Tumors often evade destruction by proteolytic shedding of MICA and MICB. Ferrari de Andrade et al. developed monoclonal antibodies that prevented tumor cells from shedding MICA and MICB, restoring NK cell-mediated antitumor immunity in immunocompetent and humanized mouse models, via both activation of NKG2D receptor by cell surface MICA and MICB, and activation of Fc receptors by the antibody itself.
MICA and MICB are expressed by many human cancers as a result of cellular stress, and can tag cells for elimination by cytotoxic lymphocytes through natural killer group 2D (NKG2D) receptor activation. However, tumors evade this immune recognition pathway through proteolytic shedding of MICA and MICB proteins. We rationally designed antibodies targeting the MICA alpha3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA and MICB by human cancer cells. These antibodies inhibited tumor growth in multiple fully immunocompetent mouse models and reduced human melanoma metastases in a humanized mouse model. Antitumor immunity was mediated mainly by natural killer (NK) cells through activation of NKG2D and CD16 Fc receptors. This approach prevents the loss of important immunostimulatory ligands by human cancers and reactivates antitumor immunity.
Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Harvard Medical School, 25 Shattuck Street, Boston, MA
Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. (2) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. (3) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. (4) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. (5) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. (6) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. (7) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. (8) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. (10) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. (11) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. (12) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. (13) Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Department of Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. (14) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. (16) Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. (17) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. kai_wucherpfennig@dfci.harvard.edu. Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.
